Cefepime versus carbapenems for treatment of AmpC beta-lactamase-producing Enterobacterales bloodstream infections.

PURPOSE: Cefepime is recommended for treating infections caused by AmpC beta-lactamase-producing Enterobacterales (AmpC-PE), though supporting evidence is limited. Therefore, this study compared outcomes associated with cefepime versus carbapenem therapy for bloodstream infections (BSIs) caused by AmpC-PE after phenotypic exclusion of ESBL-co-producing isolates. METHODS: This retrospective cohort study compared definite cefepime versus carbapenem treatment for AmpC-PE BSI in hospitalized patients of the University Hospital Basel, Switzerland, between 01/2015 and 07/2020. Primary outcomes included in-hospital death, renal impairment and neurologic adverse events; secondary outcomes included length of hospital stay and recurrent infection. RESULTS: Two hundred and seventy episodes of AmpC-PE BSI were included, 162, 77 and 31 were treated with a carbapenem, cefepime and other antibiotics, respectively. Patients treated with carbapenems were more likely to be transferred to the ICU on admission and more frequently had central venous catheter as a source of infection. In uni- and multivariable analyses, primary and secondary outcomes did not differ between the two treatment groups, except for more frequent occurrence of neurological adverse events among patients treated with carbapenems and shorter length of hospital stay among survivors treated with cefepime. CONCLUSION: After excluding isolates with phenotypic ESBL-co-production, cefepime was not associated with adverse outcomes compared to carbapenems when used to treat BSIs caused by AmpC-PE. Our study provides evidence to support the use of cefepime as a safe treatment strategy for AmpC-PE BSI, particularly in clinically stable patients without initial renal impairment or increased susceptibility to neurological adverse events.

Epidemiological study of antimicrobial-resistant bacteria in healthy free-ranging bantengs (Bos javanicus) and domestic cattle.

Background and Aim: Antimicrobial-resistant microorganisms (ARMs) have been increasing among wild animals. Interactions occurring at the interface between wildlife, humans, and livestock can lead to the transmission of ARMs. Thus, the prevalence of ARMs in wild and domestic animals should be determined to address and prevent this issue. This study aimed to determine the resistance patterns of cefotaxime (CTX)-resistant Escherichia coli and identify the presence of extended-spectrum beta-lactamase (ESBL) genes in ESBL-producing E. coli among a population of wild banteng (Bos javanicus) and domestic cattle kept on farms located close to the Lam Pao non-hunting area, Kalasin province, Thailand. Materials and Methods: Forty-five fecal samples were taken from wild bantengs inhabiting the Lam Pao non-hunting area in Thailand, alongside 15 samples from domestic cattle. Bacterial culture, triple sugar iron, and motile indole lysine tests were conducted to identify E. coli. A polymerase chain reaction (PCR) was conducted for specific confirmation. MacConkey agar supplemented with 2 µg/mL of CTX was used to identify CTX-resistant E. coli, which would be used to identify ESBL production based on a double-disk synergy test. Extended-spectrum beta-lactamase-producing samples were subjected to disk diffusion tests to determine resistant patterns, and the sizes of PCR bands and DNA sequencing were used to differentiate ESBL gene types. Results: All samples tested positive for E. coli. Forty-five isolates from 15 banteng samples and three isolates from one domestic cattle sample displayed CTX-resistant and ESBL-producing traits. The banteng and domestic cattle populations exhibited nine and three distinct resistant patterns, respectively. The PCR results indicated that the banteng isolates harbored the following genes: Cefotaxime-M1 (n = 38), CTX-M9 (n = 5), and the SHV group (n = 2). All three isolates from the domestic cattle sample contained the CTX-M1 gene. Classification of ESBL genes based on the DNA sequences of the banteng isolates showed the characteristics of CTX-M15 (n = 20), CTX-M55 (n = 6), CTX-M14 (n = 5), and CTX-M79 (n = 1). The three domestic cattle isolates exhibited the characteristics of CTX-M15, CTX-M55, and CTX-M79. Conclusion: Despite no previous antibiotic applications, approximately one-third of the banteng samples displayed CTX resistance, indicating ARM contamination within the ecosystem. The similarity in ESBL genes between the banteng and domestic cattle populations suggests potential gene transmissions between these animal groups. However, the initial source of ARMs remains unclear, as the banteng population exhibited more ESBL genes than the domestic cattle, suggesting the possibility of multiple ARM sources. These findings raise concerns because the banteng population inhabits an area that is an important source of freshwater and nourishes the entire north-east region of Thailand and other South-east Asian countries, including Laos, Cambodia, and Southern Vietnam.

Characterization of Pseudomonas aeruginosa resistance to ceftolozane-tazobactam due to ampC and/or ampD mutations observed during treatment using semi-mechanistic PKPD modeling.

A double ampC (AmpCG183D) and ampD (AmpDH157Y) genes mutations have been identified by whole genome sequencing in a Pseudomonas aeruginosa (PaS) that became resistant (PaR) in a patient treated by ceftolozane/tazobactam (C/T). To precisely characterize the respective contributions of these mutations on the decreased susceptibility to C/T and on the parallel increased susceptibility to imipenem (IMI), mutants were generated by homologous recombination in PAO1 reference strain (PAO1- AmpCG183D, PAO1-AmpDH157Y, PAO1-AmpCG183D/AmpDH157Y) and in PaR (PaR-AmpCPaS/AmpDPaS). Sequential time-kill curve experiments were conducted on all strains and analyzed by semi-mechanistic PKPD modeling. A PKPD model with adaptation successfully described the data, allowing discrimination between initial and time-related (adaptive resistance) effects of mutations. With PAO1 and mutant-derived strains, initial EC50 values increased by 1.4, 4.1, and 29-fold after AmpCG183D , AmpDH157Y and AmpCG183D/AmpDH157Y mutations, respectively. EC50 values were increased by 320, 12.4, and 55-fold at the end of the 2 nd experiment. EC50 of PAO1-AmpCG183D/AmpDH157Y was higher than that of single mutants at any time of the experiments. Within the PaR clinical background, reversal of AmpCG183D, and AmpDH157Y mutations led to an important decrease of EC50 value, from 80.5 mg/L to 6.77 mg/L for PaR and PaR-AmpCPaS/AmpDPaS, respectively. The effect of mutations on IMI susceptibility mainly showed that the AmpCG183D mutation prevented the emergence of adaptive resistance. The model successfully described the separate and combined effect of AmpCG183D and AmpDH157Y mutations against C/T and IMI, allowing discrimination and quantification of the initial and time-related effects of mutations. This method could be reproduced in clinical strains to decipher complex resistance mechanisms.

Impact of a real-time diagnostic and antimicrobial stewardship workflow on time to appropriate therapy for infections caused by multidrug-resistant Gram-negative organisms.

INTRODUCTION: Multidrug-resistant (MDR) Gram-negative organisms cause life-threatening infections, and the incidence is rising globally. Timely therapy for these infections has a direct impact on patient survival. This study aimed to determine the impact of a multidisciplinary diagnostic and antimicrobial stewardship (AMS) workflow on time to appropriate therapy (TAP) for these infections using novel beta-lactam/beta-lactamase inhibitors. METHODS: This was a retrospective quasi-experimental study of adult patients with carbapenem-resistant Enterobacterales (CRE) and multidrug-resistant Pseudomonas (MDR PsA) infections at a 1500 bed university hospital. Included patients who received ≥ 72 hours of ceftazidime-avibactam (CZA) or ceftolozane-tazobactam (C/T) from December 2017 to December 2019. During the pre-intervention period (December 2017 to December 2018), additional susceptibilities (including CZA and C/T) were performed only upon providers' request. In 2019, reflex algorithms were implemented for faster identification and testing of all CRE/MDR PsA isolates. Results were communicated in real-time to the AMS team to tailor therapy. RESULTS: A total of 99 patients were included, with no between-group differences at baseline. The median age was 60 years and 56 (56.7%) were in intensive care at the time of culture collection. Identified organisms included 71 (71.7%) MDR PsA and 26 CRE, of which 18 were carbapenemase producers (Klebsiella-producing carbapenemase = 12, New Delhi metallo-ß-lactamase = 4, Verona integron-encoded metallo-ß-lactamase = 2). The most common infections were pneumonia (49.5%) and bacteraemia (30.3%). A decrease was found in median TAP (103 [IQR 76.0-156.0] vs. 75 [IQR 56-100] hours; P < 0.001). Median time from culture collection to final susceptibility results was shorter in the post-intervention group (123 vs. 93 hours; P < 0.001). CONCLUSION: This study identified improvement in TAP in MDR PsA and CRE infections with implementation of a reflex microbiology workflow and multidisciplinary antimicrobial stewardship initiatives.

Foodborne Outbreak of Extended Spectrum Beta-lactamase Producing Shigella sonnei Associated with Contaminated Spring Onions in the United Kingdom.

Globalization of the food supply chain has created conditions favorable for emergence and spread of multidrug-resistant (MDR) foodborne pathogens. In November 2021, the UK Health Security Agency detected an outbreak of 17 cases infected with the same strain of MDR extended spectrum beta-lactamase (ESBL)-producing Shigella sonnei. Phylogenetic analysis of whole-genome sequencing data revealed the outbreak was closely related to strains of S. sonnei isolated from travelers returning to the UK from Egypt. None of the outbreak cases reported travel and all 17 cases reported eating food from a restaurant/food outlet in the week prior to symptom onset, of which 11/17 (64.7%) ate at branches of the same national restaurant franchise. All 17 cases were adults and 14/17 (82.4%) were female. Ingredient-level analyses of the meals consumed by the cases identified spring onions as the common ingredient. Food chain investigations revealed that the spring onions served at the implicated restaurants could be traced back to a single Egyptian producer. The foodborne transmission of ESBL-producing bacteria is an emerging global health concern, and concerted action from all stakeholders is required to ensure an effective response to mitigate the risks to public health.

The bactericidal effect of far-UVC on ESBL-producing Escherichia coli.

Because extended-spectrum beta-lactamase (ESBL) infections can cause life-threatening disease and effective treatments need to be developed, we examined the bactericidal effect of far-ultraviolet C (far-UVC) light therapy on ESBL-producing Escherichia coli (E. coli). The bactericidal effect on 2 types of ESBL-producing E. coli was the same as that on the wild strain although the results of drug resistance tests varied among these strains. We believe that irradiation with far-UVC is effective in preventing infection by ESBL-producing E. coli in health care settings.

A saponin-polybromophenol antibiotic (CU1) from Cassia fistula Bark Against Multi-Drug Resistant Bacteria Targeting RNA polymerase.

BACKGROUND: Gradual increase of multidrug resistant infections is a threat to the human race as MDR plasmids have acquired.>10 mdr and drug efflux genes to inactivate antibiotics. Plants secret anti-metabolites to retard growth of soil and water bacteria and are ideal source of antibiotics. PURPOSE: Purpose of the study is to discover an alternate phyto-drug from medicinal plants of India that selectively kills MDR bacteria. METHODS: MDR bacteria isolated from Ganga river water, milk, chicken meat and human hair for testing phyto-extracts. Eighty medicinal plants were searched and six phyto-extracts were selected having good antibacterial activities as demonstrated by agar-hole assays giving 15 â€‹mm or greater lysis zone. Phyto-extracts were made in ethanol or methanol (1:5 w/v) for overnight and were concentrated. Preparative TLC and HPLC were performed to purify phytochemical. MASS, NMR, FTIR methods were used for chemical analysis of CU1. In vitro RNA polymerase and DNA polymerase assays were performed for target identification. RESULTS: CU1 belongs to a saponin bromo-polyphenol compound with a large structure that purified on HPLC C18 column at 3min. CU1 is bacteriocidal but three times less active than rifampicin in Agar-hole assay. While in LB medium it shows greater than fifteen times poor inhibitor due to solubility problem. CU1 inhibited transcription from Escherichia coli as well as Mycobacterium tuberculosis RNA Polymerases. Gel shift assays demonstrated that CU1 interferes at the open promoter complex formation step. On the other hand CU1 did not inhibit DNA polymerase. CONCLUSION: Phyto-chemicals from Cassia fistula bark are abundant, less toxic, target specific and may be a safer low cost drug against MDR bacterial diseases.

Antimicrobial resistance profiles and genes in uropathogenic Enterobacteriaceae in reproductive-age women in St. Petersburg, Russia: implication for treatment of pyelonephritis in pregnancy.

BACKGROUND: Urinary tract infections (UTIs) are common in women, and during pregnancy can cause significant morbidity. Growing and greatly varying antimicrobial resistance (AMR) of Enterobacteriaceae, responsible for most UTIs, necessitates regular local AMR surveillance. In obstetric population, where beta-lactams are the mainstay for treatment of severe UTIs, particular focus should be placed on beta-lactam resistance. This study aimed to evaluate AMR rates and frequency of extended spectrum beta-lactamase (ESBL) and carbapenemase genes in uropathogenic Enterobacteriaceae among reproductive-age women in St. Petersburg, Russia. MATERIALS/METHODS: Urine samples were collected from consecutive reproductive-age women, who attended the D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology from October 2017 to November 2019, and cultured according to routine procedures. Susceptibility to antibiotics and ESBL production was determined using the disc diffusion method according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. All urine samples and Enterobacteriaceae isolates were tested for ESBL and carbapenemase genes using real-time PCR. RESULTS: Enterobacteriaceae were detected in 91 (56 pregnant and 35 non-pregnant) of 119 (76%) included women. The vast majority of Enterobacteriaceae strains were susceptible to nitrofurantoin, fosfomycin and meropenem (99-100%). The frequency of strains susceptible to penicillins and cephalosporins ranged from 59% to 82%; 78% of strains were susceptible to ciprofloxacin. ESBL production was phenotypically detected in 15 (16%) Enterobacteriaceae strains, with CTX-M genes revealed in all cases. In all corresponding urine samples, CTX-M genes were also detected. The remaining 104 urine samples were negative for CTX-M genes. In none of the isolates and urine samples, carbapenemase genes were present. CONCLUSIONS: The frequency of ESBL producing Enterobacteriaceae was relatively high (16%), with CTX-M genes detected in all cases in both urine and urine cultures. Rapid PCR detection of CTX-M genes directly in urine samples from women with pyelonephritis can be valuable for timely informing treatment choices.

Investigator-Driven Randomised Controlled Trial of Cefiderocol versus Standard Therapy for Healthcare-Associated and Hospital-Acquired Gram-negative Bloodstream Infection: Study protocol (the GAME CHANGER trial): study protocol for an open-label, randomised controlled trial.

BACKGROUND: Increasing rates of antibiotic resistance in Gram-negative organisms due to the presence of extended-spectrum beta-lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and other mechanisms of resistance are identified in common hospital- and healthcare-associated pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Cefiderocol has been shown to be potent in vitro against a broad range of Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and multi-drug-resistant (MDR) P. aeruginosa and A. baumannii. Recent clinical data has shown cefiderocol to be effective in the setting of complicated urinary tract infections and nosocomial pneumonia, but it has not yet been studied as treatment of bloodstream infection. METHODS: This study will use a multicentre, open-label non-inferiority trial design comparing cefiderocol and standard of care antibiotics. Eligible participants will be adult inpatients who are diagnosed with a bloodstream infection with a Gram-negative organism on the basis of a positive blood culture result where the acquisition meets the definition for healthcare-associated or hospital-acquired. It will compare cefiderocol with the current standard of care (SOC) antibiotic regimen according to the patient's treating clinician. Eligible participants will be randomised 1:1 to cefiderocol or SOC and receive 5-14 days of antibiotic therapy. Trial recruitment will occur in at least 20 sites in ten countries (Australia, Malaysia, Singapore, Thailand, Turkey and Greece). The sample size has been derived from an estimated 14 day, all-cause mortality rate of 10% in the control group, and a non-inferiority margin of 10% difference in the two groups. A minimum of 284 patients are required in total to achieve 80% power with a two-sided alpha level of 0.05. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected. DISCUSSION: With increasing antimicrobial resistance, there is a need for the development of new antibiotics with broad activity against Gram-negative pathogens such as cefiderocol. By selecting a population at risk for multi-drug-resistant pathogens and commencing study treatment early in the clinical illness (within 48 h of index blood culture) the trial hopes to provide guidance to clinicians of the efficacy of this novel agent. TRIAL REGISTRATION: The GAME CHANGER trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number NCT03869437 . Registered on March 11, 2019.

A comparison of E. coli susceptibility for amoxicillin/clavulanic acid according to EUCAST and CLSI guidelines.

In our tertiary care center, the reported susceptibility of E. coli blood isolates to amoxicillin/clavulanic acid exceeded 90% in 2005 and showed a progressive decrease to 50% by 2017. In this study, we investigate whether there is a real increase in resistant E. coli strains or if this apparent decline in reported susceptibility might be attributed to the substitution of CLSI by EUCAST guidelines in 2014. We randomly selected 237 E. coli blood isolates (stored at - 80 °C) from 1985 to 2018 and reassessed their MIC values, applying both the CLSI (fixed ratio of clavulanic acid) and EUCAST guidelines (fixed concentration of clavulanic acid). In parallel, the susceptibility of these isolates was retested by disk diffusion, according to the EUCAST guidelines. Whole genome sequencing was successfully performed on 233 of the 237 isolates. In only 130 of the 237 isolates (55.0%), testing according to the EUCAST and CLSI criteria delivered identical MIC values for amoxicillin/clavulanic acid. In 64 of the 237 isolates (27.0%), the MIC values diverged one dilution; in 38 (16.0%), two dilutions; and in five (2.1%), three dilutions. From these 107 discrepant results, testing according to EUCAST methodology revealed more resistant profiles in 93 E. coli strains (94.1%). Also, phenotypical susceptibility testing according to EUCAST guidelines tends to correlate better with the presence of beta-lactamase genes compared to CLSI testing procedure. This study highlights the low agreement between EUCAST and CLSI methodologies when performing MIC testing of amoxicillin/clavulanic acid. More strains are categorized as resistant when EUCAST guidelines are applied. The low agreement between EUCAST and CLSI was confirmed by WGS, since most of EUCAST resistant/CLSI sensitive isolates harbored beta-lactamase genes.

In Vivo Evolution of GES ß-Lactamases Driven by Ceftazidime/Avibactam Treatment of Pseudomonas aeruginosa Infections.

The mechanisms underlying an in vivo switch in the resistance phenotype of P. aeruginosa after ceftazidime-avibactam treatment was investigated. The initial isolate (a blood culture) was resistant to meropenem but remained susceptible to antipseudomonal cephalosporins and combinations with ß-lactamase inhibitors. One week after ceftazidime-avibactam therapy, a subsequent isolate (a rectal swab) recovered from the same patient showed the opposite phenotype. Whole-genome sequence analysis revealed a single SNP difference between both (ST235) isolates, leading to a P162S change in blaGES-5, creating blaGES-15. Thus, blaGES-1, blaGES-5, and blaGES-15 were cloned and expressed in the wild-type strain PAO1. Susceptibility profiles confirmed the P162S substitution reverted the carbapenemase phenotype determined by the G170S change of GES-5 back into the ESBL phenotype of GES-1.

Ceftolozane-tazobactam versus meropenem for definitive treatment of bloodstream infection due to extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales ("MERINO-3"): study protocol for a multicentre, open-label randomised non-inferiority trial.

BACKGROUND: Extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales are common causes of bloodstream infection. ESBL-producing bacteria are typically resistant to third-generation cephalosporins and result in a sizeable economic and public health burden. AmpC-producing Enterobacterales may develop third-generation cephalosporin resistance through enzyme hyper-expression. In no observational study has the outcome of treatment of these infections been surpassed by carbapenems. Widespread use of carbapenems may drive the development of carbapenem-resistant Gram-negative bacilli. METHODS: This study will use a multicentre, parallel group open-label non-inferiority trial design comparing ceftolozane-tazobactam and meropenem in adult patients with bloodstream infection caused by ESBL or AmpC-producing Enterobacterales. Trial recruitment will occur in up to 40 sites in six countries (Australia, Singapore, Italy, Spain, Saudi Arabia and Lebanon). The sample size is determined by a predefined quantity of ceftolozane-tazobactam to be supplied by Merck, Sharpe and Dohme (MSD). We anticipate that a trial with 600 patients contributing to the primary outcome analysis would have 80% power to declare non-inferiority with a 5% non-inferiority margin, assuming a 30-day mortality of 5% in both randomised groups. Once randomised, definitive treatment will be for a minimum of 5 days and a maximum of 14 days with the total duration determined by treating clinicians. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected. DISCUSSION: Participants will have bloodstream infection due to third-generation cephalosporin non-susceptible E. coli and Klebsiella spp. or Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens. They will be randomised 1:1 to ceftolozane-tazobactam 3 g versus meropenem 1 g, both every 8 h. Secondary outcomes will be a comparison of 14-day all-cause mortality, clinical and microbiological success at day 5, functional bacteraemia score, microbiological relapse, new bloodstream infection, length of hospital stay, serious adverse events, C. difficile infection, multidrug-resistant organism colonisation. The estimated trial completion date is December 2024. TRIAL REGISTRATION: The MERINO-3 trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number: NCT04238390 . Registered on 23 January 2020.

False amoxicillin/clavulanic acid susceptibility in Bacteroides fragilis using gradient strip tests.

BACKGROUND: Repeatedly, too low MIC results were obtained in Bacteroides fragilis quality assessment strains, using gradient strip tests with a ratio of amoxicillin:clavulanic acid of 2:1. We aimed to find the most accurate available gradient strip tests for susceptibility testing of amoxicillin/clavulanic acid in B. fragilis in comparison with agar dilution with EUCAST methodology and breakpoints. METHODS: Twenty-seven clinical B. fragilis isolates were investigated using gold standard EUCAST amoxicillin/clavulanic acid agar dilution (fixed clavulanic acid concentration at 2 mg/L, with increasing amoxicillin concentrations) as well as three commercial gradient strip tests: XL (ratio), AUG (ratio) or AMC (fixed concentration). RESULTS: Using agar dilution (fixed concentration), 19 isolates were susceptible, 1 isolate was susceptible increased exposure (I) and 7 isolates were resistant. Categorical agreement of the gradient strip tests with agar dilution (fixed concentration) was 70% for XL (ratio), 71% for AUG (ratio) and 89% for AMC (fixed concentration). Very major error rates in comparison with agar dilution (fixed concentration) were 100%, 0%, and 0%, respectively. CONCLUSIONS: EUCAST breakpoint usage in amoxicillin/clavulanic acid susceptibility tests for B. fragilis should be accompanied by EUCAST methodology. When using alternative methods such as gradient strip tests, a higher degree of alignment with EUCAST methodology, such as using fixed clavulanic acid concentrations, improves precision.

Screening and identification of bioactive components resistant to metallo-beta-lactamase from Schisandra chinensis (Turcz.) Baill. by metalloenzyme-immobilized affinity chromatography.

The screening and identification of bioactive components, which are effectively resistant to metallo-beta-lactamase (MßL), were studied in the alcohol extract of Schisandra chinensis (Turcz.) Baill. by metalloenzyme-immobilized affinity chromatography. Taking bizinc metalloenzyme beta-lactamase II from Bacillus cereus (Bc II) and monozinc metalloenzyme CphA from aeromonas hydrophila (CphA) as examples, we studied the feasibility of this scheme based on the construction of metalloenzyme-immobilized chromatographic model. It was found that the Bc II- and CphA-immobilized chromatographic column could be used not only to explore the interaction between the MßL and their specific ligands, but also to screen the bioactive components from traditional Chinese medicine. The Bc II-and CphA-immobilized columns were used to screen the bioactive components from the alcohol extract of Schisandra chinensis (Turcz.) Baill. Time-of-flight tandem mass spectrometry analysis and molecular docking revealed that isobutyl 3-O-sulfo-ß-D-galactopyranoside is the effective bioactive components that could bind with metalloenzyme Bc II. It is believed that our current work may provide a methodological reference for screening MßL inhibitors from traditional Chinese medicine.

No significant difference between ceftriaxone and cefotaxime in the emergence of antibiotic resistance in the gut microbiota of hospitalized patients: A pilot study.

BACKGROUND: Ceftriaxone and cefotaxime share a similar antibacterial spectrum and similar indications but have different pharmacokinetic characteristics. Ceftriaxone is administered once daily and 40% of its clearance is by biliary elimination, whereas cefotaxime requires three administrations per day and shows less than 10% biliary elimination. The high biliary elimination of ceftriaxone suggests a greater impact of this antibiotic on the gut microbiota than cefotaxime. The objective of this study was to compare the impact of ceftriaxone and cefotaxime on the gut microbiota. METHODS: A prospective clinical trial was performed that included 55 patients treated with intravenous ceftriaxone (1 g/24 h) or cefotaxime (1 g/8 h) for at least 3 days. Three fresh stool samples were collected from each patient (days 0, 3, and 7 or at the end of intravenous treatment) to assess the emergence of third-generation cephalosporin (3GC)-resistant Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, toxigenic Clostridioides difficile, and vancomycin-resistant enterococci. RESULTS: The emergence of 3GC-resistant gram-negative enteric bacilli (Enterobacteriaceae) (5.9% vs 4.7%, p > 0.99), Enterococcus spp, and non-commensal microorganisms did not differ significantly between the groups. Both antibiotics reduced the counts of total gram-negative enteric bacilli and decreased the cultivable diversity of the microbiota, but the differences between the groups were not significant. CONCLUSION: No significant difference was observed between ceftriaxone and cefotaxime in terms of the emergence of resistance.

An evaluation of meropenem/vaborbactam for the treatment of nosocomial pneumonia.

Introduction: Nosocomial pneumonias are the second most common healthcare-associated infections (HCAIs), often associated with the presence of Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter species, and Enterobacter species. Increasing use of carbapenems has led to an increase in the prevalence of carbapenem-resistant gram-negative organisms, such as carbapenem-resistant Enterobacterales (CRE), P. aeruginosa (CRPA), and Acinetobacter baumannii (CRAB), limiting treatment options for patients at high-risk of multi-drug resistant (MDR) gram-negative pathogens. Areas covered: The purpose of this review is to discuss the role of meropenem/vaborbactam, a beta-lactam combined with a novel non-beta-lactam cyclic boronic acid beta-lactamase inhibitor (BLI), for the treatment of nosocomial pneumonia based on its chemistry, pharmacokinetics/dynamics, microbiological spectrum of activity, mechanisms of resistance, safety, and clinical efficacy. Expert opinion: Currently, any utilization of meropenem/vaborbactam beyond its FDA-approved indication for complicated urinary tract infections is considered off-label use; however, based on the pulmonary penetration of meropenem/vaborbactam, it is highly likely to be a safe and effective alternative to more toxic agents, like aminoglycosides and polymixins, for targeted therapy in pulmonary infections due to CRE. Unfortunately, the multifactorial resistance pattern of CRPA and other non-lactose-fermenting gram-negative bacteria restricts activity against these organisms which are common pathogens implicated in nosocomial pneumonia.

Actividad antimicrobiana de ceftolozano-tazobactam y ceftazidima-avibactam contra bacilos gramnegativos clínicamente relevantes aislados en México / Ceftolozane/tazobactam and ceftazidime/avibactam antimicrobial activity against clinically relevant gram-negative bacilli isolated in Mexico

Resumen Introducción: Existe poca información acerca de la efectividad de las combinaciones ceftolozano/tazobactam y ceftazidima/avibactam en cepas clínicamente relevantes aisladas en México. Objetivo: Determinar el perfil antimicrobiano de ambos antibióticos en nuestra comunidad. Método: El presente estudio de investigación fue prospectivo, descriptivo y transversal. Se incluyeron cepas clínicamente relevantes aisladas a partir de cultivos de cepa pura durante el periodo de agosto de 2018 a enero de 2019 en Mexicali, Baja California, México. Resultados: Se analizaron 74 cepas de enterobacterias y 19 cepas de Pseudomonas aeruginosa; el porcentaje de sensibilidad de ceftazidima/avibactam fue de 100 % contra enterobacterias y de 72.7 % contra Pseudomonas aeruginosa; el porcentaje de sensibilidad de ceftolozano/tazobactam fue de 90.5 % para enterobacterias y de 72.7 % para Pseudomonas aeruginosa. Conclusiones: Las combinaciones ceftolozano/tazobactam y ceftazidima/avibactam ofrecen buena sensibilidad antimicrobiana in vitro, tanto contra enterobacterias productoras de betalactamasas de espectro extendido como contra Pseudomonas aeruginosa. Se requieren más datos para valorar la respuesta clínica en pacientes que reciben esas combinaciones de antibióticos.

Abstract Introduction: There is limited information on the effectiveness of ceftolozane/tazobactam and ceftazidime/avibactam combinations on clinically relevant strains isolated in Mexico. Objective: To determine the antimicrobial profile of both antibiotic combinations in our community. Method: The present research study was prospective, descriptive and cross-sectional. Clinically relevant strains isolated from pure-strain cultures were included during the period from August 2018 to January 2019 in Mexicali, Baja California, Mexico. Results: 74 enterobacteriaceae and 19 Pseudomonas aeruginosa strains were analyzed; the percentage of sensitivity of ceftazidime/avibactam was 100 % for enterobacteriaceae and 72.7 % for Pseudomonas aeruginosa; the percentage of sensitivity of ceftolozane/tazobactam for enterobacteriaceae was 90.5 % and 72.7 % for Pseudomonas aeruginosa. Conclusions: The ceftolozane/tazobactam and ceftazidime/avibactam combinations offer good antimicrobial sensitivity in vitro, both for ESBL-producing enterobacteriaceae and Pseudomonas aeruginosa. More data are required to assess clinical response in patients receiving these antibiotic combinations.

Andrographis paniculata extract inhibit growth, biofilm formation in multidrug resistant strains of Klebsiella pneumoniae.

BACKGROUND AND AIM: Andrographis paniculata (Kalmegh), a valuable ancient medicinal herb is used in the treatment of several diseases in most Asian countries including India. Klebsiella pneumoniae is an opportunistic pathogen causing nosocomial infections in human. We have investigated the antimicrobial susceptibility and the presence of AmpC gene in K. pneumoniae strain isolated from the sputum of the patient. EXPERIMENTAL PROCEDURE: Antibiotic susceptibility test and phenotypic detection of AmpC/ESBL beta-lactamase were performed by combined disc diffusion test. The CEA of A. paniculata was analyzed for its antibacterial potential against susceptible and resistant strains of K. pneumoniae through the broth microdilution method. Molecular detection of AmpC gene was carried by polymerase chain reaction (PCR). RESULTS: Antibiotic susceptibility test displayed that the clinical isolate of K. pneumoniae were resistant towards cephalosporins, quinolone and monobactam but susceptible to carbapenems. Combined disk diffusion demonstrated AmpC+ve/ESBL-ve beta-lactamase. 250 µg/ml of CEA extract confirmed the inhibition of bacterial growth and biofilm formation compared to the antibiotic. CEA treated K. pneumoniae displayed a reduction of AmpC by polymerase chain reaction. CONCLUSION: The present study illustrates that CEA extract of A. paniculata demonstrated potentiality to control K. pneumoniae growth and biofilm formation. CEA was able to suppress the expression of gene encoding AmpC. This study proves to be an economical approach to control the growth of K. pneumoniae which causes serious infections.

The changing resistance patterns of bacterial uropathogens in children.

BACKGROUND: Increased antimicrobial resistance is a problem in managing urinary tract infections (UTI). With this study we assessed the resistance patterns of urinary isolates in children with UTI between January 2017 and January 2018. METHODS: A retrospective cohort study was conducted. Among 5,443 isolates, a total of 776 UTI episodes in 698 patients were included. Patients' gender, age, voiding dysfunction, UTI history, prophylaxis status, and presence of vesicoureteral reflux were noted. Patients were divided into three age groups: group 1 for ages ≤12 months; group 2 for ages 13-60 months; and group 3 for ages >60 months. The susceptibilities of etiologic agents to different antimicrobials were explored. RESULTS: Median age was 54 months (range 1 month-21 years); male to female ratio was 1:5. The most common causative agent was Escherichia coli (83% of the cases), followed by Klebsiella pneumoniae (7.5%). Resistance to ampicillin (62.6%) and co-trimoxazole (39.8%) were remarkable in all isolates. Overall extended-spectrum beta-lactamase (ESBL) positivity was 23.5%. The highest resistance rates, higher ESBL positivity (28.6%), and K. pneumoniae frequency (13.5%) were observed in group 1. Ceftriaxone resistance was significantly low (0.5%) in the ESBL (-) group, which constituted the majority of the isolates. Higher resistance rates were observed among the patients on prophylaxis compared to those off prophylaxis (P < 0.001). CONCLUSION: Ceftriaxone can still be used for empirical treatment; however, initial urine culture results are crucial due to high ESBL positivity. Special consideration must be taken for patients under 1 year of age. Periodical surveillance studies are needed to explore the changing resistance patterns of uropathogens and modify treatment plans.

Characterization of AmpC ß-lactamase mutations of extensively drug-resistant Pseudomonas aeruginosa isolates that develop resistance to ceftolozane/tazobactam during therapy.

INTRODUCTION: We characterized AmpC ß-lactamase mutations that resulted in ceftolozane/tazobactam resistance in extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates recovered from patients treated with this agent from June 2016 to December 2018. METHODS: Five pairs of ceftolozane/tazobactam susceptible/resistant P. aeruginosa XDR isolates were included among a total of 49 patients treated. Clonal relationship among isolates was first evaluated by pulsed-field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) was further performed. AmpC mutations were investigated by PCR amplification of the blaPDC gene followed by sequencing. RESULTS: The ST175 high-risk clone was detected in four of the pairs of isolates and the ST1182 in the remaining one. All resistant isolates showed a mutation in AmpC: T96I in two of the isolates, and E247K, G183V, and a deletion of 19 amino acids (G229-E247) in the other three. The G183V mutation had not been described before. The five isolates resistant to ceftolozane/tazobactam showed cross-resistance to ceftazidime/avibactam and lower MICs of imipenem and piperacillin/tazobactam than the susceptible isolates. CONCLUSIONS: Ceftolozane/tazobactam resistance was associated in all of the cases with AmpC mutations, including a novel mutation (G183V) not previously described. There is a vital need for surveillance and characterization of emerging ceftolozane/tazobactam resistance, in order to preserve this valuable antipseudomonal agent.